Immune Response Ebook

Have you ever wondered WHY you get sick from different things, sometimes seemingly for no reason? Haven't you ever wished that you could find some way to stop yourself from getting sick and stay healthy all the time? Well, that might be more possible than you thought at first! Your immune system is an odd system, that many scientists are still struggling to understand. However, there have been some amazing breakthroughs! Once you get access to this detailed and helpful book, you will be able to find REAL and Applicable ways to improve your immune system and keep yourself from getting sick all of the time. This book teaches you everything that you never learned about your immune system Start learning what you can Really do to improve your immune system's health and keep your body healthier for longer! It's not hard at all Get started today! Read more...

The lymphoid system can be conceptually divided into a central and a peripheral system. The central system generates the lymphocytes from stem cells in the bone marrow and provides for further differentiation of B cells in the bone marrow and T cells in the thymus. The peripheral lymphoid system, on the other hand, is where the lymphocytes and accessory cells initiate adaptive immune responses. Peripheral lym-phoid organs include tonsils, peripheral lymph nodes, spleen, and the mucosal lymphoid systems. In most lymph nodes, as well as in the spleen, lymphocytes are concentrated in the white pulp. T cells are found in the central region and B cells are found in the germinal centers, which are toward the periphery of the organ or node.1-3 Cell Types of the Adaptive Immune Response Many different cell types (see Fig. 11-3) participate in the various types of immune responses. Conventional B-cell development (B-2, not B-1) occurs totally within the bone marrow. As stem cells reproduce...

Immune responses, initiated as outlined earlier, are subject to regulation that for antimicrobial immunity selects elements of the immune system adapted to contain specific pathogens and also regulates immune responses to minimize damage to surrounding cells and tissues due to uncontrolled inflammatory reactions.1-3 Although it was speculated for some time that there might be a subset of regulatory T cells (TR), it was not until these cells could be identified by cell surface markers that definitive studies could be performed. In both mice and humans, the major population of TR is CD25+, CD4+. CD25 is the a-chain of the high affinity IL-2 receptor. TR have rearranged T cell receptors and are antigen specific many of them react with host antigens. Once activated, the TR secretes IL-10 and TGF-0 and suppresses the immune response nonspecifically. The importance of TR has been shown in mice and humans. Mice that are depleted of CD25+, CD4+ lymphocytes rapidly develop autoimmune disease...

The vast majority of infectious diseases are caused by pathogens that infect mucosal surfaces or use them as portals of entry. Mucosal immune responses are the first line of defense against these pathogens that are inhaled, ingested, or sexually transmitted. However, some agents may be able to breach these defenses, and go on to cause systemic disease. Therefore, vaccines against these agents may need to induce both mucosal and circulating immune responses for optimal protection (1-3). The systemic and mucosal immune systems communicate, but are somewhat compartmentalized (1-3). In general, induction of immune responses via systemic immunization supports systemic responses. Under appropriate conditions, mucosal introduction of foreign substances (antigens) can induce both mucosal and systemic responses. Following oral delivery, for example, antigens or invading pathogens, which can survive the harsh acid and degradative environments encountered, may be taken up by the specialized...

The adaptive immune system contains two major arms. The cellular arm leads to the production of CTLs, also called killer T cells. The humoral arm leads to the production of antibodies that are secreted by B cells. T-helper cells are important players in generating these responses. Immune System Players

A number of reviews available in the literature detail the cellular and molecular mechanisms by which vitamin A may influence immune function (Semba, 1998, 1999 Stephensen, 2001) to complement these, there is a comprehensive review of the effects of ''vitamin A supplementation on immune responses as well (Villamor and Fawzi, 2005). Briefly, vitamin A is believed to be important at all levels of the immune system (Ross and Stephensen, 1996 Semba, 1998) its various functions include maintaining the integrity of the epithelia, increasing the levels of acute phase reactants in response to infection, regulating monocyte differentiation and function, improving the cytotoxicity of natural killer cells, enhancing the antibody responses to tetanus toxoid (Semba et al., 1992) and measles vaccines (Coutsoudis et al., 1992), and increasing the total lymphocyte count, especially the CD4 subset. Similarly, various other vitamins regulate cellular and humoral immune function at a variety of levels....

A wide class of Lotka-Volterra type of systems arises in the study of host-parasite dynamics. A typical example is virus immune system competition but epidemiology is closely related too. We now explain how differential systems can be extended to structured population systems in the case of virus dynamics. The next section treats epidemiology. The intent is mainly to give examples where the structuring variable has a physiological meaning (these are referred to as physiologically structured), besides the traditional space structure already mentioned for invasion fronts in Sections 1.1 and 1.3. 1.4.1 Virus dynamics, immune response Describing the immune response of a single individual is a domain full of differential equations. A simple idea is that virusses represent the prey and leukocytes are the predators, then a model like the prey-predator system of Section 1.2.2 is satisfactory. However many other effects have to be added. In the case of the competition between a tumor and the...

As stated, Toxoplasma free-GPIs elucidate strong and early immunogenic responses during host infection. Data from other protozoa suggest that other functions of GPIs in host immune response are possible. In Plasmodium falciparum, the GPI moiety, free or associated with protein, induces tumor necrosis factor and interleukin-1 production by macrophages, and regulates metabolism in adipocytes (Schofield and Hackett, 1993). Deacylation with specific phospholipases abolishes cytokine induction. When administered to mice in vivo the malaria parasite GPI induces cytokine release, a transient pyrexia and hypo-glycemia, and profound and lethal cachexia, in the presence of sensitizing agents. The data suggest that the GPI of Plasmodium is a potent glycolipid toxin that may be responsible for a novel pathogenic process. It has been further demonstrated that Plasmodium GPI directly and specifically increases cell adhesion molecule expression in HUVECs, and parasite cytoadherence (Schofield et...

It has long been known that stressful conditions can suppress immune functions, reducing the ability of an individual to recover from infection. This can be explained by the fact that the neuroendocrine and immune systems are interconnected, forming an integrated system with common mediators and receptors. Cells of the immune system have receptors for many hormones, hormone-releasing factors and neurotransmitters - evidence that these molecules regulate immune responses. Moreover, immune cells themselves produce hormones and endorphins. The interplay between the neuroendocrine and immune systems is bi-directional, as exemplified by the control of Cortisol release from the adrenal glands during stress. Cortisol has well-known anti-inflammatory properties and it also suppresses the immune system. The signal for the release of cortisol originates in the brain. Electrical signals generated in the brain, and also IL-1 and IL-6 synthesized in brain cells, stimulate the hypothalamus to...

(pollen, animal hair, chemicals, etc.) and to unwanted cells or cell products arising within the body from cancer or autoimmune diseases. The immune system comprises (1) cellular defence mechanisms mediated by several types of leucocytes and (2) humoral defence mechanisms mediated by soluble proteins, so-called because they are dissolved in the body fluids rather than being primarily associated with cells. Any immune response involves, firstly, recognition of the pathogen or other foreign material and, secondly, elimination of these invaders. When an immune response occurs in an exaggerated or inappropriate form, the term 'hypersensitivity' is applied. The fundamental concept underlying the function of the immune system is the ability to distinguish, at the molecular level, 'self' from 'non-self' (foreign) materials. All cells of the immune system originate from just one cell type in the bone marrow of adult mammals, the haemopoietic stem cell. These pluripotent cells give rise to two...

An important outcome of virus infection in a vertebrate host is the development of a virus-specific immune response triggered by the virus antigens. Regions of antigens known as epitopes bind to specific receptors on lymphocytes, activating cascades of events that result in the immune response. Lymphocytes are the key cells in specific immune responses. There are two classes of lymphocyte B lymphocytes (B cells), which develop in the Bursa of Fabricius in birds and in the bone marrow in mammals, and T lymphocytes (T cells), which develop in the thymus. Each lymphocyte is specific for a particular in the immune system have receptors for the Fc region of IgG (Figure 9.3), allowing these cells to attach to antibody-coated virions and cells. Cell types that have IgG Fc receptors include Helper T cells secrete specific cytokines and are characterized by the presence of CD4 molecules at the cell surface. Helper T cells play essential roles in the initiation of immune responses, for example...

Intravesical immunotherapy using BCG was first proposed by Morales et al. 49 in 1976. Conventional prophylactic regimes of 6 weekly instillations, similar to those used for chemotherapy, resulted in complete response rates of 60 to 100 at 1 year, 55 to 75 after 2 years, and mean recurrence-free intervals of 10 to 22.5 months 50 . Although the long-term response rates with BCG are less enduring, the reduction in recurrence appears to be better than the rates achieved using most chemotherapy agents. This superiority is supported by comparative studies of BCG and anthracycline agents, which suggest that BCG has a roughly twofold advantage over Adriamycin and epirubicin (with an overall BCG tumor recurrence rate reduction of approximately 30 ) 51 . In contrast, trials comparing MMC directly with BCG have been less consistent in outcome, and passionately debated. Of the published comparative MMC-BCG studies, three have suggested that MMC may have therapeutic equivalence to BCG for patients...

Efficient immune response requires activation of CD4+ T cells. Adoptive immunotherapy combining tumor-specific CD4+ and CD8+ lymphocytes is more efficient than the sole CTL transfer (Antony, 2005). CD4+ T lymphocytes were the first target of Treg suppression identified in vitro (Thornton and Shevach, 1998) and are also consistently inhibited in vivo. Casares et al. (2003) have shown in a murine tumor model that Treg depletion restores IFN-7 production by CD4+ T cells and results in both CD8-dependent and CD8-independent protection from tumor growth. The reactivity of CD4+ T lymphocytes in the presence of tumor is detectable only after proper immunostimulation. Otherwise, these lymphocytes are kept in a strict state of anergy by tumor-derived immunosuppressive signals and fail to produce cytokines upon ex vivo restimulation (Cuenca et al., 2003). A consistent portion of such unresponsive CD4+ lymphocytes is phenotypically and functionally regulatory cells and includes not only...

Several observations have contributed to the idea that prolactin may be an important regulator of hematopoiesis and immune function in mammals. First, both the prolactin receptor and ligand have been identified in cells of the hematopoietic system (52-56). Second, pharmacological studies in animals and clinical correlations in humans have shown that prolactin alters parameters of hematopoiesis and immune function (57-61). Third, certain cells cultured from hematopoietic lineages respond to prolactin in vitro (62). Fourth, the prolactin receptor and downstream signaling molecules are homolo gous with proteins that mediate the actions of a variety of hematopoietic cytokines (13). Despite these types of evidence, it has remained difficult to reconcile the idea that prolactin is an essential immunoregulatory hormone with the fundamental requirements of its role in reproduction. prolactin is secreted at much higher levels in females than in males, and at highly variable levels at different...

Another avenue of research in HRPC is immunotherapy, which is dependent on a suitable target antigen being presented to the immune system by an antigen-presenting cell (APC), such as the dendritic cell. The dendritic cell was chosen specifically because it is the most potent in eliciting a T-cell immune response. This approach has been evaluated in a randomized, placebo-controlled, phase III trial in HRPC patients with the drug APC8015. This is a product consisting of autologous dendritic cells loaded ex vivo with a recombinant fusion protein of prosta-tic acid phosphatase linked to granulocyte-macrophage colony-stimulating factor. This treatment was well tolerated and antigen-specific immunity was evident, but only in the subset of patients with a low Gleason score was there a trend toward improvement in median time to progression. A confirmatory phase III trial in these patients is now underway 53 . Vaccine-based therapies are also being evaluated. In one randomized phase II study,...

Following V cholerae O1 infection, robust serum vibrio-cidal antibody responses and rises in immunoglobulin G (IgG) cholera antitoxin are observed.60,61 Approximately 90 of complement-dependent vibriocidal antibodies are directed toward the O antigen with the remaining 10 to 15 of antibodies being against protein antigens. In immunologically primed individuals, strong SIgA intestinal antibody responses are recorded following cholera infection. However, significant rises in SIgA anti-LPS and antitoxin are surprisingly sparse in nonprimed individuals. The detection of gut-derived, trafficking IgA antibody-secreting cells that make specific antibody to LPS and CT antigens is a good measure of priming of the intestinal immune system.62

The answer is c. (Murray, 5 e, p 93.) Most of the antibody produced in a primary immune response is IgM. As time passes or at a second encounter with the same antigen, isotype (class) switching can occur. 6. The answer is c. (Murray, 5 e, p 110-111.) Innate immunity involves antigen-nonspecific immune defense. Neutrophils circulate in the blood and can migrate into tissue to ingest and kill bacteria. Although T and B cells can augment the innate immune response, they become inactivated in an antigen-specific manner. Eosinophils, also part of the innate immune response, are important in parasitic, rather than bacterial, infections. 11. The answer is b. (Roitt, 5 e, p 168.) The fetus and newborn infant can only produce measurable IgM antibody in response to infection. If IgG is detected, it is the result of an immune response by the mother and the antibody has crossed the placenta. 12. The answer is d. (Murray, 5 e, p 88, 121.) Usually an immunogen contains more than one molecule that...

The innate immune system is composed of a large number of elements that attempt to control infection by pathogens, but this system is independent of the identity of the particular pathogen. Complement is a component of the innate system as well as the adaptive system and has been described. Other components of the innate system include the cytokines, a complicated set of small proteins that are powerful regulators of the immune system. Many cytokines are critical for the function of the adaptive immune system, as described in part above. Cytokines are also important components of the innate system. The innate system also

The human immune system has evolved in concert with microbes and is very sophisticated, especially with regard to host defenses against microbes, but the system is not perfect. Interactions of the immune system with microbes are an ongoing affair. Microbes have a high mutation rate compared to human beings. Microbes have evolved a diversity of mechanisms that can enable microorganisms to subvert immediate immunologically mediated elimination. Persistence within the host is necessary for the propagation of some parasites. There are multiple mechanisms by which microbes can persist in the body and evade the immune system. Tolerance is defined as specific reduction in the response of the immune system to a given antigen.101,102 In the case of transplacental infection, the fetus develops a certain degree of tolerance to antigens to which it is exposed. The immune system of fetuses is rather incompletely developed in utero, and microorganisms survive easily. Cytomegalovirus infects the...

Some mechanisms of adjuvant action are discussed below, and which are summarized in Table 2. Vaccine adjuvants can (1) increase the potency of small, antigenically weak synthetic or recombinant peptides. (2) They can enhance the speed, vigor, and persistence of the immune response to stronger antigens. For example, aluminum adjuvants used with licensed pediatric vaccines (e.g., DTP) elicit early and higher antibody response after primary immunization than do unadjuvanted preparations. (3) Adjuvants can increase the immune response to vaccines in immunologically immature, immunosup-pressed, or senescent individuals. (4) Adjuvants can select for, or modulate humeral or cell-mediated immunity, and they can do this in several ways. First, antigen processing can be modulated, leading to vaccines that can elicit both helper T cells and cytotoxic lymphocytes (CTL) (reviewed in 7,43 ). Second, depending upon the adjuvant, the immune response can be modulated in favor of MHC class I or MHC...

Gastrointestinal infections have a particularly important role in inducing a compromise in host nutritional status. Malabsorption in gastrointestinal illness may result from the epithelial destruction by the pathogen or by the immune response to the pathogen. Even common diarrheal illnesses can have a profound impact on nutrient absorption. In symptomatic rotavirus infection, the most common cause of acute severe diar-rheal illness worldwide, there is a 42 decrease in the absorption of nitrogen and fat, a 48 decrement in the absorption of carbohydrates, and a 55 decrease in the total energy absorp-tion.122 These indices for malabsorption are slightly more severe in both ETEC infections and shigellosis.25,122 In shigellosis,123 protein loss is sizable and important, and vitamin A is wasted.27 Giardiasis and ascariasis lead to the malabsorption of vitamin A.24 Large losses of zinc also occur in diarrhea.124

Attachment domains by which the virus binds to a susceptible cell. This activity is thought to be related to the ability of many viruses, nonenveloped as well as enveloped, to bind to and agglutinate red blood cells, a process called hemag-glutination. The protein possessing hemagglutinating activity is often called the hemagglutinin or HA. The viral glycoproteins also possess a fusion activity that promotes the fusion of the membrane of the virus with a membrane of the cell. The protein possessing this activity is sometimes called the fusion protein, or F. The glycoproteins, being external on the virus, are also primary targets of the humoral immune system, in which circulating antibodies are directed against viruses many of these are neutralizing antibodies that inactivate the virus.

One of the clinical problems in immunocompro-mised hosts is recrudescence of the infection resulting in stage conversion back to actively proliferating and tissue-destructive tachyzoites. To examine the situation in the immunocompetent host, the brains of immunocompetent chronically infected mice have been examined. It is found that, indeed, a very small percentage of tissue cysts are rupturing at any given time during chronic infections (Ferguson et al., 1989). The initial change appears to be the death of the host cell. With the exposure of the parasite antigen in the cyst wall, there is evidence of a rapid and massive cell-mediated immune response involving numerous inflammatory cells (monocytes and even neutrophils). These are observed around the still apparently intact cyst (Figure 2.25A). With the rupture of the cyst wall, there is a further influx of macrophages into the cyst (Figure 2.25C). The macrophages phagocytose the bradyzoites, where there is fusion with lysosomes...

The side effects of systemic immunosuppres-sion are common and can be serious and life threatening. The immune system is an integral part of our defence against the outside world and its suppression leads to vulnerability. It is difficult to identify the precise relationship between a particular agent and a specific side effect. The drugs are usually used for patients with serious systemic disorders and often in combination with other powerful agents. Some of the side effects encountered are non-specific in that they are a consequence of the immuno-suppression. Others are due specifically to a particular agent.

Host resistance to parasitic infection is very similar to the resistance shown against bacteria. The immune system works by the formation of antibodies against a limitless amount of substances recognized as foreign antigens by the B lymphocytes. These blood cells, due to constant mutation, are much different from each other in such a manner that the system contains myriads of coded lymphocytes. When a parasite meets with one of these B lymphocytes that have a specific antibody against its antigen, the lymphocyte reproduces at a high rate to produce plasma cells. When these second generation antibodies encounter the antigens coating the parasites, a neutralization process takes place that kills the invaders. Immunity against parasites can be inherited or acquired. The acquired immunity may be natural or artificial, while the artificial can be active or passive.

To initiate immune responses, antigens must be recognized by naive T cells in order to activate them to effector cells. According to the present concept, two signals are necessary for the activation of T cells. Besides the correct recognition of a presented antigen (signal 1) by the interaction of the specific T-cell receptor, the peptide antigen and the antigen presenting MHC-class-II molecule on the APC, the presence of co-stimulatory signals (signal 2) such as CD80 86, CD40 or ICAM-1 on the APC is required. This is necessary to initiate the production of a sufficient amount of the cytokine interleukin-2 (IL-2) by the T cell that is required for the autocrine stim- Fig. 6.3. Basic functions of the mucosal immune system. One of the main functions of the mucosal immune system is the maintenance of a fine equilibrium between inflammatory immune protection against microbial infection and the generation of tolerance to the majority of non-pathogenic antigens that occur at mucosal...

The effects of neem on the immune system are complex and have not been fully elucidated some evidence points to an immunostimulant effect, while other evidence suggests it can also act as an anti-inflammatory. The latter may be partly explained by inhibition of prostaglandin synthetase (Van der Nat et al., 1991 Okpanyi and Ezeukwu, 1981 Obaseki et al., 1985). However, Kroes et al. (1993) showed that in a classical Ayurvedic preparation for gout, nimba arishta, the anti-inflammatory activity is almost entirely attributable to ingredients other than neem. Here we review the evidence for the immunostimulant effects of neem, and to what extent this may explain its perceived efficacy in the treatment of malaria. There is a small amount of evidence that neem may boost both the humoral and the cell-mediated immune responses to malarial infection, but it comes mostly from mice, which may have different immune responses from man, and in which neem has not been shown effective against malaria....

Roll motif and a C-terminal P-trefoil domain (see Chapter 2). This latter domain, comprising 150 amino acid residues, shows very little sequence homology among the different serotypes, suggesting that this domain may be principally responsible for determining serotype specificity. There is some evidence, however, that both halves of the Hc domain are required to elicit neutralizing antibodies and that accurate folding of the entire domain is essential. Vaccinating mice with only the N-terminal half, of the Hc domain, only the C-terminal half, or a mixture of the two failed to produce a notable protective immune response.55

The traditional induction regimen of six weekly instillations of chemotherapy,initiated a week after resection, was based on original work using BCG immunotherapy. Delayed bladder instillation was intended as a prophylactic therapy for a secondary new occurrence, presuming that all previous tumors have been eradicated. It is now increasingly apparent that intravesical chemotherapy is best intended as an ablative therapy to mop up loose cells released at the time of extirpation and to prevent tumor reimplantation. Longitudinal studies have shown that tumor recurrences occur in two time-dependent peaks. The groups with early recurrence peaks are sensitive to chemotherapy, whereas those with delayed recurrences are generally resistant 35 . It is not surprising, therefore, that the influential study of the MRC demonstrated that immediate instillation of MMC within 24 hours of transurethral resection was as effective as conventional 6-week courses 61 . Indeed, more recent studies have...

It has been hypothesized that anchorage of a peptide in a liposomal bilayer might mimic the normal presentation of antigen on an infectious agent (i.e., multivalent and projecting outward from an anchor on the surface of the cell) and thereby potentiate the immune response to the peptide. To test this hypothesis, peptides were covalently linked to a phospholipid, providing a hydropho-bic anchorage into the phospholipid bilayer. Current concepts regarding the mechanisms through which peptide epitopes are presented to CD8+, major histocompatibility complex (MHC) Class I -restricted cytotoxic T lymphocytes (CTL) indicate that a crucial aspect of this process is the capacity to introduce antigen into the cytoplasm (but not endosomes) of antigen-presenting cells (18). This explains, at least in part, the success of live-attenuated and live-vector vaccines for stimulating cell-mediated immune responses.

Employing cell culture systems which are reconstituted with B7-H1-expressing cell lines, B7-H1 and PD-1 blocking antibodies and tumor-specific T cells, experimental data unequivocally support the idea that tumor-associated B7-H1 negatively affects T-cell functions in multiple aspects, including inhibition of T-cell proliferation, T-cell production of IL-2 and IFN7, promotion of IL-10 production and suppression of cytolytic activity of tumor-specific CD8 T cell (CTL) (Dong et al., 2002). In several mouse tumor models in vivo, tumor-associated B7-H1 induces CTL apoptosis or confers resistance to lysis by CTL. In addition, B7-H1+ tumors are shown to be resistant to T-cell adoptive-transfer immunotherapy or therapeutic antibody anti-CD137. Furthermore, B7-H1 was shown to be necessary for the maintenance of T-cell exhaustion in a chronic infection mouse model of lymphocytic choriomeningitis virus (LCMV). Recent in vivo anergy tolerance models also reveal a critical role of B7-H1-PD-1...

Pertinent permissive cell cultures, such as retinal glial cells or retinal pigment epithelial cells, have been used to study HCMV replication (Fig. 10.2). Virus replicates slowly and progressively 11,16 . In the era of highly active anti-retroviral therapy, intraocular inflammation, like cystoid macular edema, vitritis or papillitis, has been reported in patients presenting with completely cicatricial retinitis. It was therefore of interest to analyse different pathways involving antiviral immune responses that might potentially play a role in these situations. The model of retinal pigment epithelial cells was used to analyse virus-host interactions. The occurrence of HCMV retinitis in the late phase of immunosuppression may be related to perturbation of cytokine production and secretion, associated with the progressive loss of the CD3+CD4+ cell subset. The effects of different cytokines such as IFN-g, IFN-p, IL-1P, TGF-p and TNF-a, which are present in the eye under different...

To date, BCG remains the treatment of choice for CIS disease. Although cytotoxic chemotherapy agents have shown initial response rates as good as 48 using anthracyclines and 53 for MMC, most series have demonstrated that this response is time limited, with fewer than 20 remaining disease free at 5 years 72 . This apparent chemoresistance may well reflect the high grade of CIS disease, whereas higher grade may imply greater antigenicity and therefore susceptibility to BCG immunotherapy. Bacille Calmette-Guerin therapy gives complete response rates of 60 to 70 with a median duration beyond 3 years and projected 5-year responses of 45 . Nevertheless, 30 to 40 of patients with CIS disease do not respond to a single induction course of BCG 72 . The response rates and the durability of response may be improved with maintenance therapy. Advocates of long-term maintenance refer to the SWOG 8507 study (see above) 69 ,although this was not specific for CIS. Further credence to maintenance BCG...

Neonates are highly susceptible to infectious diseases (Kovarik and Siegrist, 1998). In clinical trials in newborn babies, VA supplementation on days 1 and 2 after birth reduced neonatal mortality in the first 2 months of life, especially in infants of low birth weight (Rahmathullah et al., 2003). The VA status, in terms of liver VA reserves and plasma retinol of newborns, even full-term infants of well-nourished mothers, is low as compared to that of older children and adults. Thus, neonates might well be considered physiologically VA deficient, or as of marginal VA status (Ross, 2005). Neonates are known to respond poorly to conventional vaccines due to immaturity of the immune system (Siegrist, 2001), and this has stimulated a search for better adjuvants for neonatal vaccines. As indicated in Table I, the pattern of immune deficiency reported for neonates (Marshall-Clarke et al., 2000) resembles the pattern observed in VA-deficient adult rats and mice (Ross, 1996a), with low...

For others, allowing the body to self-heal meant bolstering the immune system. For example, in talking about how she treats her husband's colds, Laura said, I'll give him Echinacea or suggest he use some vitamin C or garlic to boost his immune system. Lindsay also believes in the value of strengthening the immune system to allow the body to heal itself I wanted to find if there was a way that I could strengthen my own body constitution so that it could fight off the infections more. So when I'm starting to feel sick, hopefully my immune system will kick whatever it is off sooner.

Recurrences in AIDS patients under maintenance therapy, or in the setting of a partially functional immune system, may show little evidence of activity. The leading edge creeps progressively closer to the fovea (Fig. 11.5). Diagnosis of such progression necessitates a sharp clinical acumen, or preferably a close comparison of the current clinical picture to fundus photos taken some time before. If photos cannot be taken, the chart should document the relationship between the leading edge of the lesion and neighbouring landmarks such as vessels.

Liver, a proportion of the newly absorbed chylomicron retinyl ester is taken up into extrahepatic tissues, especially tissues that express lipoprotein lipase and are active in the metabolism of chylomicron triglycerides. Additionally, some of the newly absorbed VA is oxidized in the intestine and absorbed as RA into the portal system (Ross, 2006). Newly absorbed VA and intestinally formed metabolites may have a metabolic fate different from that of retinol bound to retinol-binding protein. It was shown in studies of chylomicron metabolism that chylomicron-associated VA is taken up, in an apparently transient manner, by bone marrow (Hussain et al., 1989a,b). However, the implications of this uptake process for hematopoiesis and immune function have not been studied. It is also interesting that, among several large-scale community trials on the effect of VA on child mortality, the study showing the largest reduction in all-cause mortality, 54 (Rahmathullah et al., 1990), delivered VA as...

Patients with the genetic disorder X-linked severe combined immunodeficiency (X-SCID) have been successfully treated with retroviral vectors. The procedure involves taking stem cells from the patient and infecting them with a recombinant retrovirus, the genome of which contains a good copy of the gene that is defective. If the vector provirus is integrated into the cell genome, and if the good copy of the gene is expressed, then the patient is able to develop a normal immune system. The successes, however, have been tempered by the development of cancer in a few treated patients.

A subsequent trial carried out at the M.D. Anderson Cancer Center involved administration of intravesical adenoviral p53 to patients not considered suitable for cystectomy 4 .Three different doses and three regimens of repeated dosing were used and again very little toxicity was seen. Biopsies were taken at 4 to 16 days posttreatment, and unfortunately only 7 of 13 were suitable for RT-PCR to detect the p53 transgene. Two patients were found to express the transgene, and both had received the highest dose (1012 viral particles). One of the reasons for the apparently lower level of successful transfec-tion in this study may be that less tissue was available for analysis. Also while the previous study used a polyamide in an effort to increase penetration of the GAG layer, this was not the case in this trial. Although only a phase I trial, one patient was described who seemed to have significant tumor regression after p53 therapy. Histology revealed a potent cell-mediated immune...

The answer is d. (Schwartz, 7 e, pp 97-98.) Most transfusion reactions are hemolytic and are due to clerical errors that result in administration of blood with major (ABO) and minor antigen incompatibility. Interestingly, Rh incompatibility is not associated with intravascular hemolysis. Administration of blood through hypotonic solutions such as 5 dextrose and water results in swelling of the erythrocytes and hemoly-sis. Calcium-containing solutions such as Ringer's lactate cause clotting within the intravenous line rather than hemolysis and may lead to pulmonary embolism. Delayed transfusion reactions, caused by a presumed anamnestic immune response that occurs 3-21 days after blood is infused, result in a hemolytic anemia.

Pneumococcal disease was the first infection to be prevented by a nonprotein vaccine. Due to the work of Griffith, Tillet, Finland, Heidelberger, MacLeod, and Austrian, the capsular polysaccharide has come to be recognized as a critical component of vaccine efficacy (reviewed in Musher and associates109 and Broome and Breiman110). The geographic distribution of serotypes differs by region, making a universal vaccine based on a reasonable number of capsular types complicated and costly to compose.111 The currently approved vaccines consist of the capsular polysaccharides from 23 of the most common serotypes.110 After many comprehensive studies, there is now overwhelming evidence that this vaccine is approximately 60 efficacious for protection against invasive disease in the general population, but it fails to protect the segments of the population most susceptible to disease children younger than the age of 2 years or the elderly who are medically compro-mised.110,112-114 The vaccine...

The unique structure of the skin allows it to perform a number of specialized functions. One fundamental function of the skin, in particular the stratum corneum, is to provide an essential barrier to penetration of environmental chemicals by limiting their diffusion into the skin (Madison, 2003 Monteiro-Riviere, 2004). In addition, cells in the viable epidermis are able to metabolize compounds that penetrate the stratum corneum and thereby moderate toxicity (Bronaugh et al., 1994 Steinstrasser and Merkle, 1995). The skin also presents a barrier to penetration of sunlight (Kornhauser et al., 2004). About 60 of incident sunlight in the damaging UVB (290-320 nm) region of the spectrum is reflected at the skin's surface or absorbed in the stratum corneum. Light that enters the viable epidermis is further attenuated by scattering and through absorption by epidermal chromophores such as melanin, proteins, and urocanic acid. Because of the constant exposure of skin to a diverse set of...

These clinical scenarios in our view are still valid reasons to perform a nephrectomy in the presence of metastatic disease. However, recently randomized trials have provided us with data that argues more strongly for nephrectomy prior to cytokine therapy in the setting of metastatic disease. Certain immunotherapy trials have required patients to have a nephrectomy prior to trial entry. The rationale for this approach is that reduction of tumor burden may increase the likelihood of response. This biological argument is supported by animal data showing that the large bulk of primary tumor is either immunosuppressive or acts as an immunological sink with suppression of cell-mediated immunity that is reversed upon removal of the primary tumor 21,22 . Improvements in human immune responses have also been demonstrated postnephrectomy 23 . Removal of the primary also gives the possibility of harvesting tumor infiltrat status, the site of metastases, and the presence of measurable disease....

Over150 different M types of GAS are recognized, based either on antibody recognition typing of the M protein expressed or by sequencing of the emm gene itself. M protein is a coiled a helix consisting of four regions of repeating amino acids (A-D) A proline-glycine-rich region serves to intercalate the protein into the bacterial cell wall, and a hydrophobic region acts as a membrane anchor. Region A near the N-terminal is highly variable, and antibodies to this region confer type-specific protection, likely due to enhanced opsonization of the M protein.29 Within the more conserved B-D regions lies an area that binds one of the complement regulatory proteins (factor H). The net effect is to stearically inhibit antibody binding and complement-derived opsonin deposition, thus effectively camouflaging the organism against immune surveillance. M protein also inhibits the phagocytosis of S. pyogenes by PMNs, though this property can be overcome by type-specific antisera. Kotb and...

Typically, the ability of a virus to move systemically is assessed by measuring the levels of viral proteins and or genomes in systemic tissues. The absence of viral products in uninoculated, systemic leaves, with a normal level of local accumulation in the inoculated leaf, is presumed to be based on SAR and or blocked systemic movement. Traditionally, when the possible involvement of SAR and hypersensitive reactions can be ruled out, the absence of virus in systemic leaves is postulated to be due to a block in viral systemic movement. However, recent progress in understanding molecular mechanisms of the plant innate immune response by RNA silencing and its inhibition by RNA silencing suppressors encoded by many plant viruses (reviewed in Baulcombe 2001 Baulcombe 2002, 2004 Bisaro 2006 Dunoyer et al. 2005 Scholthof 2005 Soosaar et al. 2005) has revealed that some of the seemingly blocked viral

The inflammatory response is mediated by chemicals released from cells of the tissue and from cells of the immune system. An important early phase mediator is histamine, which is released from the storage granules of mast cells and also by platelets within seconds of initiation. Later, about 6-12 hours after initiation, vascular events are mediated by prostaglandins and leukotrienes, which are products of arachidonic acid metabolism. These molecules are newly synthesized and secreted by a wide variety of cell types in response to an appropriate stimulus. Cytokines (Section 5.5) are important in signalling between cells as inflammatory reactions develop.

The Nef (Negative regulatory factor) protein acquired its name because it was originally thought to have an inhibitory effect on HIV replication, though later work showed that this protein stimulates replication In infected cells Nef alters the endosome trafficking pathway, reducing expression at the cell surface of CD4 and MHC class I and II proteins. These changes can shield HIV-infected cells from immune surveillance.

The predominant cell type in the acquired immune system is the lymphocyte - a non-phagocytic, motile cell which is found mainly in the lymphoid tissues. Unlike cells of the innate immune system, which have non-specific recognition systems, lymphocytes have unique antigen-recognizing receptors inserted into their plasma membranes, enabling the lymphocytes to recognize specific pathogens. Therefore, before exposure to antigen, there exists in an individual vast numbers of lymphocytes, each with a different antigen-binding specificity governed by the molecular conformation of its receptor. In the absence of an immune response, lymphocytes are in an inactive or 'resting state'. When an immune response is triggered, for example during a virus in fection, lymphocytes that can respond to the virus become activated to carry out their specific functions. After they have been activated, the lymphocytes proliferate and become much larger cells called lym-phoblasts. Activation signals that...

For some purposes hamsters (Frenkel et al., 1975 Gormley et al., 1998) or rats (Foulet et al., 1994 Dubey, 1996 De Champs et al., 1997 Kempf et al., 1999 Zenner et al., 1999b Freyre et al., 2001b, 2003b, 2004) have been used, but usually not for drug evaluation. Models are based on a primary acute infection of the animals, on direct inoculation of the parasite into the animal brain with or without immunosuppression, or on a chronic infection of the animal that may be immunosuppressed (for example with immunosuppressive drugs or radiation, antibodies directed against lymphocytes or cytokines, or concomitant infections with viruses that modulate the immunosystem) (see Tables 7.5 and 7.6). For certain applications, the use of genetically modified mice with various defects in their immune system may also be an option. In general, the acute and strictly localized models have most often been used to evaluate the treatment efficacy of antiparasitic drugs, whereas the chronic infection models...

By retinoid ligands is known to influence many of the biological responses of the skin. Three of these functions (the immune response, wound healing, and aging) will be briefly discussed below. In addition to receptor mediated effects, evidence is emerging that vitamin A can elicit nonligand effects. The role of vitamin A in mediating some effects of UV light on the skin is discussed below as an example of a nonligand effect of vitamin A.

Weakly expressed in non-stimulated cells, ICAM-1 expression is strongly increased by pro-inflammatory cytokines such as IL-ip, IFN-y and TNF-a, as well as by bacterial lipopolysaccharides and phorbol esters. ICAM-1 interacts with lymphocyte-function-associated antigen-1 (LFA-1), a member of the P2 subfamily of integrins, which is constitutively expressed by lymphocytes and other cells of the immune system. In addition to its role in adhesion and extravasation of T cells, the LFA-1 ICAM-1 adhesion system is important for antigen presentation (Altmann et al., 1989).

Inducible Cre expression is extremely useful in the analysis of the role of certain genes in adult animals, because it offers the opportunity of gene modification after the completion of the normal development of the organism or of its adaptive cell systems, such as the neuronal and the immune system. Although constitutive cell-specific Cre expression can be achieved with the

Soluble antibodies are Y-shaped glycoproteins of the immunoglobulin (Ig) family synthesized and secreted by plasma cells in response to antigenic stimulation of naive B cells. Occurring freely in the blood and lymph, antibodies act as flexible adapters, allowing various mediators of the immune system to recognize specific pathogens and their products and to exert their action. The body can make several million different antibodies, each one able to recognize a specific infectious agent. All antibody molecules consist of four polypeptide chains - two identical heavy chains and two identical light chains. Each of the arms of the Y-shaped molecule represents a Fab region, which binds to antigen the stem represents the Fc region, which interacts with immune system mediators. The terminal half of each of the Y arms is highly variable in its amino acid sequence from one antibody to the next, the remainder of the molecule being relatively constant. These differences give rise to the terms...

Furthermore, a cancer-causing cell often looks much like an ordinary human cell on a molecular scale and it seldom offers any unique biological target, against which a small-chemical drug may specifically act. This difficulty in distinguishing normal cells from cancerous and virus-infected cells also makes it hard to treat certain diseases through immunization - that is, the activation of the body's natural immune response. And most chemotherapeu-tic agents that target DNA have powerful but adverse side-effects on healthy cells. Similar kinds of transgenic experiment are now being conducted extensively worldwide to make 'improved' animals or plants. For example, various genes have been added to pigs not only to make them grow fatter or faster for agricultural purposes, but also (and somewhat incredibly) to modify cell surfaces along their bodily organs, so that pig organs will not be rejected by the human immune system, if they are transplanted by surgery into...

All the particles (virions and non-infectious particles) are much more abundant in the blood than in the liver, and the non-infectious particles, especially the spheres, vastly outnumber the virions. Presumably the virus has a good reason for inducing the production of such large amounts of non-infectious material, but that reason is not understood. It has been suggested that it might be a decoy for antibodies, thereby providing virions with some protection from the host's immune system.

A few animal models of CM have been developed (53), but the one established by G. E. Grau et al. (54) in mice using P. berghei ANKA has been instrumental in demonstrating the contribution of the immune system and TNF to CM pathogenesis. This model results from the parenteral injection of P. berghei ANKA-pRBR into mice of susceptible strains, such as the CBA Ca or the C57Bl 6. It consists of an acute syndrome dominated by neurological signs (paralysis, ataxia, convulsions) that arises 6-9 d after infection and is invariably lethal 12-36 h after onset. The injection of P. berghei ANKA-pRBR into mice of resistant strains, such as the BALB c, does not result in any acute syndrome or early mortality, but in a state of chronic anemia that is lethal during the fourth week of infection. The finding that athymic nude mice are protected against CM initially suggested that the immune response is responsible for the development of CM (55). This hypothesis was then largely confirmed and expanded...

Assuming that the plants are claimed to be efficient in treating malaria in a broad sense, there are many alternatives to deal with such a situation, and this has been explained in the integrated approach to antimalarial plants (Rasoanaivo et al., 2002). Particularly, the possible stimulation of the immune system of the infected host by antimalarial extracts is a relevant area to explore further (Foldes and Matyi, 1994 Murata et al., 1999). In some cases, successive treatments with various plants are frequently done until the patient is cured thus, possible additive or synergistic activities should also be considered.

The renal cancer population is relatively heterogeneous whether evaluated by conventional histology, prognostic models, site of metastasis, or novel markers. This leads to difficulty in selecting promising approaches based on isolated responders in early-phase trials. Through most of the period of testing, many of the compounds are available for clinical use only in investigational trials. Often the trials have entrance criteria that appear restricted to a fraction of the available, interested population. A common pattern in 2005 is zero or one previous immunotherapy treatment, and clear cell subtype only, and no central nervous system (CNS) metastasis history. For the individual patient seeking a particular compound, a working knowledge of trial databases such as cancer.gov, www.nkca.org, and regional cancer

The immune response, as it may relate to the spectrum of disease forms in leprosy, may be summarized as follows In tuberculoid leprosy the response is that of Th1-like T cells, and in lepromatous leprosy there is a Th2 response producing cytokines IL-4 and IL-10.83 These different immunologic responses of the host determine, in large measure, the different

The first-generation adenoviral vectors discussed so far are not suitable to obtain long-term gene expression. This is generally attributed to downregulation of the CMV promoter and to an immune response to virus-infected cells. These infected cells are recognized by the immune system since some of the adenoviral backbone genes, despite the absence of the early regulator switch E1, are clearly expressed. If the expressed transgene is also highly immunogenic (such as the bacterial lacZ gene), this will further contribute to the immune response.

Immunosuppression physiologically occurs in immune-privileged organs like testis, placenta and eye. Furthermore, some pathological conditions like tumorigenesis can use mechanisms providing immune privilege to escape from the host immune response. Treg are involved in both physiological and pathological suppression of immune reactivity. Moreover, though natural Treg display a TCR repertoire mainly directed toward self-antigens (Hsieh et al., 2004), they suppress not only auto-reactive but also allo-geneic immune responses therefore, they might counterbalance anti-tumor immunity regardless of the targeted antigens, either tumor-associated self-antigens or tumor-specific non-self-molecules. In recent years, the role of Treg in the intricate network characterizing tumor-associated immune tolerance has been extensively investigated. Despite an incomplete understanding of their biology, the involvement of Treg in tumor immune escape remains undoubted.

Activation of the immune system by Gram-negative bacteria, their products, or both can result in a cascade of events leading to endotoxic shock, a situation in which large amounts of cytokines, such as tumor necrosis factor a (TNFa), interleukin (IL)-1 and IL-6, as well as other inflammatory mediators, are produced. If unaltered, these events frequently lead to death. Endotoxin lipopolysaccharide (LPS), a component of the cell wall of Gram-negative bacteria, was identified many years ago as a major mediator that triggers the massive cellular and humoral responses observed in shock induced by Gram-negative bacteria (1). The toxic effects of LPS are mediated by factors produced by host cells, mainly TNFa, as shown by the protective effects of TNF antibodies (2). There are two other points in favor of a role of TNFa in Neutralizing monoclonal anti-TNF antibodies provided protection against shock during lethal bacteremia induced by Escherichia coli infusion in baboons, indicating that...

Toxins are chemical compounds of biological origin. Their origin and their ability to affect the human immune system separate them from other poisons. The advent of biotechnology has changed the magnitude of the toxin threat. Toxins that are only available in small amounts in nature can be produced in large quantities using bioengineering techniques. Bioengineering may also allow subtle changes in the toxins that do not alter their toxic properties but decreases the body's natural ability to neutralize the toxins. The ability to produce large quantities of toxins, the ability to manipulate their structure, and the ability to target them for specific cells have greatly increased their potential as effective biological warfare agents.

Because of its central role in tumor suppression, p53 and its pathways have been recognized as a prime target for developing new cancer therapies 13, 24, 27, 35, 40, 46, 58, 64 , and various strategies have been pursued. Wild-type p53 may be delivered through gene therapy approaches regardless of the p53 status of the cancer 3, 19, 71, 83, 92, 105 . Cancer cells lacking p53 function can be specifically targeted with mutant adenovirus 6, 63 or adeno-associated virus 80 . Inactive wild-type p53 and some p53 cancer mutants may be reactivated through targeting of the very carboxy-terminal putative autoregulatory domain of p53 with antibodies 1, 33, 41, 72 or peptides spanning part of this region 2, 42, 86 . If MDM2 overexpression is responsible for p53 inactivation, the inappropriate interaction between MDM2 and p53 may be disrupted by peptides and compounds 21, 40, 87 . The pursuit of this strategy has resulted in very potent small-molecule inhibitors of MDM2 54, 94 . Yet, all these...

IgM antibody, in contrast, arises early in infection and then disappears within a couple of months. IgM is intravascular and does not cross the pla-cental barrier. For this reason, infants with specific IgG responses to disease must be tested for IgM to determine whether their immune systems have produced antibody or whether the test was positive because of passively transferred IgG.

The interaction of viruses with their hosts is intimate and the product of a long period of evolution during which viruses coevolved with their hosts. Humans cannot survive without a functioning immune system to protect them from viruses. However, this is the result of the long evolutionary history during which hosts and viruses adapted to one another, because viruses in turn cannot survive without their hosts. The example of rabbit myxoma virus demonstrates that the virulence of a virus diminishes if it kills too large a proportion of its hosts too rapidly. We can even speculate that the exceptional virulence of the influenza virus responsible for the 1918 pandemic might have been made possible because of active warfare ongoing at the time. Very ill and dying soldiers continue to be moved about and the virus could continue to spread, perhaps could even spread more readily, if it incapacitated its hosts. On the other hand, the many examples of ways in which viruses modify the immune...

Immunochemical detection methods are based on the reaction between antibodies and antigens. The production of antibodies is an immune system response to alien substances (the antigen). The type of antibody produced is often antigen-specific. It is this specific relationship between antibody and antigen that can be utilized as a tool in fungal identification (Gobel et al., 1998 Hahn et al., 1998). Antibodies, produced by exposing an animal's immune system to a specific antigen, are coupled by chemical means to molecules which can be easily detected, such as fluorescent dyes for fluorescence microscopy, enzymes for enzyme-linked immunoassays, or heavy metals for immunocytochemical analysis with an electron microscope (Harlow and Lane, 1988 Gobel et al., 1998 Hahn et al., 1998). Labelled antibodies introduced into a system in which the fungal symbiont is unknown will recognize and bind to their corresponding antigen (providing it is present). Schmidt et al. (1974) were among the first to...

Inactivated, or killed, virus vaccines are made by mass producing the virulent virus and then inactivating the infectivity, usually by treatment with a chemical such as formaldehyde (Section 23.5.2.c). The trick lies in finding the combination of chemical concentration and reaction time that completely inactivates the virus, but leaves its antigens sufficiently unchanged that they can still stimulate a protective immune response.

Chickens vaccinated with pure neuraminidase heads were protected from death by lethal avian influenza viruses. But whether this protection was due to inhibition of neu-raminidase activity or to enhanced clearance of the virus by the immune system was not established (Webster et al., 1988).

There are many functions of vitamin A. Along with vision, vitamin A is important for reproduction, immune function, growth, bone development, cellular differentiation, proliferation, and cell signaling. Vitamin A is particularly important for normal epithelial cell (surface cell) function and integrity. These epithelial cells affected by vitamin A include the intestinal cells, skin cells, urogenital cells, and lung cells. Within the last 20 years, there has been an increased interest in vitamin A, as discoveries have highlighted the importance of vitamin A in maintenance of normal lung function and prevention of injury.

Traditionally, more than 40 of patients with RCC have died from their cancer, in contrast to the approximately 20 mortality rates associated with prostate and bladder carcinomas 16 . In addition, as for other relatively radioresistant solid tumours for which as yet there are no chemotherapy or immunotherapy treatments of proven and significant efficacy, surgery represents the only therapeutic option that is able to affect and favourably alter patient survival and prognosis of the disease. A subgroup of patients with special characteristics concerning prognosis and a surgically challenging condition are those where the renal tumour is associated with extension of a thrombus into the inferior vena cava (IVC) (5 ), with the extension possibly reaching above the diaphragm and into the right atrium (1 ) 14 .

Viruses as Vectors to Elicit an Immune Response No human vaccines have been licensed that use such recombinant viruses, but there are ongoing clinical trials of several potential vaccines. Several trials of candidate vaccines against HIV have been conducted that use vaccinia virus or retrovirus vectors to express the HIV surface glyco-protein. These trials have been moderately successful in the sense that immune responses to HIV glycoprotein were obtained, but it is not known if the immune response is protective. Studies in monkeys with related vaccines against simian immunodeficiency virus have given mixed results. In most such trials, immune responses were generated, but these were not fully protective. One recent trial did generate a protective response, however, giving hope that continued efforts in this direction will ultimately work out. A very recent study with anti-HIV drugs given very soon after infection found that limiting the replication of the virus early appears to allow...

Force to breach skin (as in needle penetration), and has made sensation-free clinical manipulation (containment, preparation, and breach) of skin tissue difficult (4). In general the new skin breach technologies described in this communication require either direct uniaxial application of mechanical energy or thermally mechanically induced changes in the physical properties or structure of skin. They differ from classical approaches in that they attempt to target the epidermis and upper dermal layers devoid of nosiceptors while gaining access to the circulatory and immune systems via the dermal capillary bed and epidermis, respectively. If successful, these approaches may greatly reduce or eliminate the mechanical stimulation of pain responses during delivery.

Stat1-deficient mice also display increased incidence of tumor formation compared to wildtype mice when challenged with the carcinogen methylcholanthrene or when bred onto a p53-deficient background (Kaplan et al., 1998b). The increased tumor incidence may be a result of a failure of immune surveillance presumably related to impaired IFNy signaling, since IFNy receptormice also have an increased incidence of methylcholanthrene-induced tumors. Another potential mechanism for tumorigenesis in Stat1 null mice is defective TNF-induced apoptosis and constitutively reduced expression of caspases (Kumar et al., 1997). Additionally, a third mechanism may be via the antiangiogenic effect of IFNy on tumors (Coughlin et al., 1998).

Molecules containing the CNGRC motif are expected to target murine as well as human angiogenic vessels (36,51). Thus, human NGR-TNF might be expected to have better antitumor properties than human TNF in patients, based on what we observed with mouse NGR-TNF in animal models. Findings from murine models suggest that doses required for antitumor effectiveness in humans are at least one order of magnitude higher than the maximum tolerated dose. Thus, it is possible that targeted delivery of TNF to aminopeptidase N could contribute to overcoming this problem. Moreover, NGR-TNF cDNA could be used for gene therapy in place of the TNF gene (64), and biotinylated NGR-TNF could be used, in principle, in tumor pretargeting with biotinylated antibodies and avidin to further increase its therapeutic index. Because tumor debulking with targeted TNF is associated with induction of protective immunity in our models, one appealing possibility is that this approach could be useful to reduce the tumor...

Currently, more than 400 human somatic cell gene therapy protocols are being tested. Most of these involve the use of genetically modified cells to treat noninherited diseases. For example, normal copies of the p53 tumor suppressor gene are inserted into lung tumors to halt tumor progression, and genetically modified cells have been used to create new coronary vessels in patients with coronary heart disease. Success has also been achieved in the treatment of hereditary disease (most notably, the recent successful treatment of X-linked severe combined immune deficiency see Clinical Correlate).

Virulence in mice is the most recognized phenotypic marker type I strain led to a widespread parasite dissemination and death of mice less than 10 days after inoculation of 10 tachyzoites in contrast, mice survived to infection with a type II strain (50 percent lethal dose (LD50) 103) and tachyzoite dissemination was much less extensive. Type III is also generally considered as avirulent in mice, although progressive deterioration and death of mice, notably with neurological symptoms, can occur a few weeks or months after inoculation. The genetic differences between strains elicit a different immune response in the host that could in part explain the different patterns of

Leishmaniasis, pentavalent antimonials in a single dosage of 850 mg monthly is recommended for prophylaxis. In mice infected with L. major, the progression of the illness has been prevented or there has been partial protection with recombinant IL-12 and CD40L (Immunity 1996 4(3) 283-9). In the anergic form and in kala-azar a usefull alternative is immunotherapy with BCG plus killed Leishma-nia promastigotes. Immunotherapy Immunotherapy Immunotherapy 2 Convit J, Castellanos Putrich M, et al. Immunotherapy of localized, intermediate and diffuse forms of American cutaneous leishmaniasis. J Infect Dis 1989 160 (1) 104-15.

At the turn of the century, there was much debate as to the mechanism by which yellow fever spread. The Department of the Army sent an expedition, under the command of Walter Reed, to Cuba, recently acquired by the United States from Spain, to study the disease. The commission undertook to test the thesis that the virus was transmitted by mosquitoes, using themselves as human volunteers. Mosquitoes were allowed to feed on yellow fever patients and then on volunteers. At first there was a lack of understanding about the fact that mosquitoes are infected only by feeding on patients early in their disease, before an effective immune response arises, and about the necessity for an extrinsic incubation period in the mosquito, during which the virus establishes an infection in the salivary glands, before it can transmit the virus. Ultimately, however, the investigation team did succeed in proving mosquito transmission and one member of the commission, Dr. Jesse Lazear, died of it....

There are multiple human host defense mechanisms acting all along the human gastrointestinal tract that help prevent infection by foodborne bacterial pathogens. These include non-specific defenses against all bacteria as well as defenses specific to particular pathogens that are part of an adaptive immune response. Some of the body's non-specific defenses include the acidic pH and proteolytic enzymes in the stomach, detergents and flushing action in the small intestine, as well as competitive microflora in the large intestine. The human host also combats foodborne bacterial pathogens using innate and adaptive immune responses generated via interaction between pathogen and the intestinal mucosa. In this way, the human intestine acts as a key player in the development of healthy immune functioning. A major component of intestinal immunity, responsible for generating a specific adaptive immune response to foodborne pathogens, is gastrointestinal-associated lymphoid tissue (GALT), which...

FIGURE 5-1 A schematic representation of the interactions between infectious diseases and malnutrition. These two-way interactions between infectious disease and malnutrition include direct consequences of the infecting microorganisms and indirect (or secondary) effects that involve the immune system and other antigen-nonspecific host defensive organisms. NAIDS, nutritionally acquired immune dysfunction syndromes. FIGURE 5-1 A schematic representation of the interactions between infectious diseases and malnutrition. These two-way interactions between infectious disease and malnutrition include direct consequences of the infecting microorganisms and indirect (or secondary) effects that involve the immune system and other antigen-nonspecific host defensive organisms. NAIDS, nutritionally acquired immune dysfunction syndromes.

During an immune response, the antigen receptors on a given T cell are engaged by antigen presented in the correct context on the surface of an APC. T-cell activation requires a sufficient number of TCR engagement and signaling events to overcome response thresholds. In mature T cells, the level of Ikaros activity sets activation thresholds and regulates G0-G1-S transitions. In Ikaros-mutant T cells, where Ikaros activity is reduced, fewer TCR engagements are required to drive a quiescent T cell into the cell cycle, and the mutant cells progress more quickly through G1 to S. Similarly, B cells with reduced levels of Aiolos activity require fewer BCR engagements to become activated. The top bar represents the cell cycle progression of wild-type murine T cells while the bottom bar depicts the shortened G1 of Ikaros-mutant cells. Below the top bar are immunofluorescence confocal microscopy images showing the nuclear staining patterns of Ikaros in wild-type T cells at the...

The decision to opt for conservative (bladder-sparing) treatment obligates the use of adjuvant BCG immunotherapy, despite an acceptance that the impact of BCG therapy on G3pTl tumors has been difficult to assess. This is due in part to the limited number of patients with G3pTl disease available for study (who will accept enrollment in a study arm with no adjuvant therapy), but also to the interdependence of other factors such as concomitant CIS, tumor multifocality, tumor size, and previous recurrence rates. The non-standardization of BCG treatment protocols has also limited direct comparisons of data. Historical reports of response rates following BCG therapy have varied from 25 to 75 for recurrence and 7 to 54 for progression 76-78 . Important differences would account for the large variation in responses. For example, in Herr's 76 1991 series, where progression rates were high (54 ) all the selected patients had Table 13.4. Recent studies of BCG immunotherapy for G3pT1 disease...

A simplified scheme of infection-related oncogenesis can be used to categorize the malignancies into one of two types either tumors caused by the integration of oncogenic DNA into the host cell or those induced by chronic inflammation. Basically, all types of oncogenic agents enhance cell growth. The mechanisms by which this occurs can be quite variable, however, ranging from expression of viral oncogenes for cell growth factors to stimulation of growth by inflammatory intermediaries. Agents with oncogenes, however, directly immortalize cells, while inflammatory carcinogenic agents do not. Moreover, it is thought that immunosuppression may be important for development of malignancies related to oncogene integration. This is not thought to be the case for inflammation-related malignancy in fact, immunosuppression, by lessening the inflammatory response, could potentially protect against inflammation-related cancers. This was highlighted in a recent review by Smukler and Ratner who...

Once activated, type I receptors phosphorylate and activate the intracellular signaling proteins known as Smads. Smad2 and Smad3 have been identified as downstream phosphorylation targets of activated type I receptors in the TGF - and activin-signaling pathways. Homozygous Smad2-null mutant mice die during embryogenesis (49-51). At least two lines of Smad3-null mutant mice have been generated by homologous recombination. Mice in which exon 8 is deleted are viable, but die between 1 and 8 mo of age because of compromised immune function (52). Mice in which exon 2 of Smad3 is deleted are also viable, but develop metastatic colorectal adenocarcinomas between 4

The administration of HAART to AIDS patients has dramatically changed the course of CMV disease by improving the function of the immune system and increasing survival 37,55 . If CD4 cell counts increase after HAART, a beneficial effect on viral recurrences may be observed and anti-CMV maintenance therapy can be discontinued 69 . In patients presenting with previous areas of CMV retinitis before immune restitution under HAART, episodes of posterior uveitis, vitritis, retinal vasculitis, papillitis and macular edema have been reported 12, 38 . The patho-physiology of disease, known as immune recovery uveitis, remains controversial 57 . However, personal data and results reported recently seem to exclude viral replication and highlight an immune reaction due to restoration of lymphocytes recognizing chronically infected retinal cells expressing CMV antigens at their surface.

The lesions may persist and be very serious in patients with a compromised immune system. While the virus may regress, it does not disappear. The lesions caused by the virus do disappear, however. Also, it is important for dental specialists to recognize that this may be a very serious infection when it occurs in immuno-compromised patients (AIDS, renal transplant, cancer chemotherapy, and so forth).

Most often, molluscum contagiosum is an asymptomatic infection, although when the immune system mounts an inflammatory reaction itching can occur. Mol-luscum contagiosum in adults primarily affects the genital, perianal, groin, upper thigh, and lower abdomen. The eruption is characterized by multiple pearly lesions, at least some of which show umbilication (Fig. 6). Often these are shiny and appear nearly vesicular, leading to the lay term water warts.'' The central umbilication contains a white, cord-like core. The lesions vary in size but are generally 1 to 3 mm. Histologically, molluscum bodies are cytoplasmic inclusion bodies within keratino-cytes that contain large numbers of mature virions. The papule consists of acanthotic epithelium with hyperkeratosis. In the immunocompetent host, they often resolve without treatment within one to two years. Immunocompromised individuals may have lesions that are unusually large, numerous, and resistant to treatment.

Interest in new methods of potentiating the immune response against vaccine antigens has increased considerably over the past decade. In part, this interest is in response to vaccine initiatives that have established aggressive goals for improving existing vaccines and for developing much-needed new vaccines. Many of the candidate vaccine antigens being developed as part of this effort are synthetic or recombinant subunit structures that are often poorly immunogenic and as such, are unable to elicit protective immune responses in the absence of an adjuvant. Fortunately, our understanding of disease patho-genesis and the immunological mechanisms of protection have increased considerably over the past few years, thus providing an improved rational basis for the development of new adjuvants. A promising candidate adjuvant in this setting is MPL immunostimulant, a monophosphoryl lipid A preparation derived from the lipopolysaccharide (LPS) of Salmonella Minnesota, R595 (1,2). The...

Jenner vaccinated people by placing a drop of vaccinia-containing solution on the skin and then scarifying the skin in some way, allowing the virus to replicate in this region. Vaccinia virus infection is localized to the area inoculated in the vast majority of people, leading to a localized lesion that results in a pock. This vaccination procedure gave solid immunity against smallpox but because of the limited replication of the virus in humans, the immunity was not considered to be lifelong and periodic reimmunization was practiced. Vaccinia virus has been used to immunize hundreds of millions of people over the years. It is generally safe, but infection of a small fraction of people results in a more serious disease. In people whose immune system is impaired, progressive vaccinia may develop because the individual cannot control the replication of the virus, which results in a fatal illness. Generalized cutaneous vaccinia can also result from inoculation or, very rarely,...

A 19-year-old man presents to the emergency department with pneumonia. Since the age of 6 months, he has had recurrent pneumonia and sinusitis due to Streptococcus pneumoniae and Haemophilus influenzae. Careful assessment of his immune function would likely reveal abnormal function of the

Biofilm attach themselves to the polysaccharide matrix or to the bacterial cells beneath them. Adherence via a biofilm is a very effective mechanism used by bacteria to avoid several of the host defenses aimed at preventing enteric infection. For example, the majority of bacteria in a biofilm are protected under several layers of extracellular polysaccharide matrix and, therefore, are not easily flushed away or easily accessed by secretory antibodies, bacteriocidal enzymes, phagocytic immune system cells or antibiotics (Donlan and Costerton, 2002). Adherence via biofilms can contribute to persistence of an infection. Prouty et al. (2002) for example, demonstrated that Salmonella enterica can form biofilms on gall stones and thus cause chronic infection and be continually shed. Finally, the changes in gene expression that occur as a result of living in a biofilm often enhance stress resistance and may facilitate virulence. For example, biofilm-producing strains of Enterococcus faecalis...

Cent of patients recovered, but for the remainder the infection proved to be lethal. These were mainly individuals who had an underlying condition such as diabetes, heart disease or a weakened immune system. On the face of it SARS is a respiratory tract disease, but in many patients the infection spread to other parts of the body. Diarrhoea developed in some patients and the virus was shed in the faeces and urine for several weeks.

The major histocompatibility complex (MHC), also designated HLA for human leukocyte antigen, is expressed on the surfaces of a large variety of cells and is translated from a region of highly polymorphic genes.1-3 A number of very elegant studies in mice led to the MHC's being recognized as responsible for immune responses, and the region to which these genes mapped was called the Ir region for immune response genes.35 These genes were subsequently shown to be necessary for activation of helper T lymphocytes, which are necessary for the production of T-dependent antibody. Later it was recognized that T cells do not recognize free or soluble antigens, but rather peptides of antigens that are bound to MHC. The MHC has two types of gene products class I and class II. Class I consists of a transmembrane heavy chain, which is complexed to soluble P2-microglobulin. All cells, with the sole exception of erythrocytes, express class I. Class II is composed of an a and P transmembrane chain and...

Alternatively to the use of inducible transgenic expression vectors, Cre can be delivered to somatic tissues through infection of mice with viral expression vectors (Table 4). These Cre-expressing viruses can be applied either locally, infecting the cells around the injection site, or by intravenous injection reaching many cells, mainly in the liver and spleen. Viral vectors can be applied at a given time point into adult mice, but they do not act in a cell type-specific manner and elicit a strong immune response against infected cells.

Thus, adjuvants administered repeatedly as nonspecific enhancers of immune response are largely excluded. Immunopotentiating agents administered to humans separately in time or location from the vaccine may be impractical for vaccinating large numbers of persons, and potentially unsafe because of their physiological effects on the entire body. They may have a role, however, in immunizing a small number of high-risk, immunocompetent individuals, such as renal dialysis patients at risk for hepatitis B or the very elderly at risk of influenza. Examples of such whole body adjuvants used in humans to augment vaccines include Na diethyldithiocarbamate (13), thymosin alpha one (14), loxoribine (15), granulocyte-macrophage stimulating factor (16,17), cimetidine (18), and dehydroepiandrosterone sulfate (19). The results of such trials to date have been disappointing. Several terms used in Table 1 need to be defined. A carrier has several meanings it is an immunogenic...

Until then, adjuvants in general had been characterized mainly by their ability to raise high antitoxin titres. In contrast, FCA proved to be a highly efficient stimulator of cell-mediated immunity in addition to its ability to augment the humoral immune response. FCA, however, had a profile of adverse side-effects (Table 1), severe enough to restrict its use to experimental immunology in laboratory animals. A modified version of FCA is known as Freund's incomplete adjuvant (FIA). In this formulation the antigen is administered in a similar water-in-oil (W O) emulsion, but without mycobacterial components. With FIA, an excellent stimulation of the humoral immune response was still

Transcutaneous immunization (TCI), the introduction of antigens using a topical application to intact skin, is a new technology that has both practical and immunological merits. Practically speaking, a needle-free method of vaccine delivery will decrease the risk of needle-borne diseases, reduce the complications related to physical skin penetration, improve access to vaccination by eliminating the need for trained personnel and sterile equipment, and provide a simple means for multivalent or multiple boosting immunization. The immunological implications of TCI are profound as this technique appears to target highly accessible antigen presenting cells (APC) in the skin that can be exploited for a variety of immune outcomes. It has been our experience that TCI can be reliably and reproducibly conducted with a variety of antigens to induce potent and functional immune responses. Thus, this new method may significantly impact both the delivery of vaccines and open new possibilities for...

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